T. Heinrich, H. B€ottcher / Bioorg. Med. Chem. Lett. 14 (2004) 2681–2684
2683
R'
(CH2)3CO2H
R''
6
1
2
5
4
HO2C
HO
HO2C
HO
HO2C
R
a
b
46%
80%
N
NH2
NH
N
3
H
EtO2C
13, R = OH; R' = H; R'' = CO2Me
14, R = H; R' =OH; R'' = CO2Me
15, R = OH; R' = H; R'' = CO2H
16, R = H; R' =OH; R'' = CO2H
{
{
11
12 (CH2)4
c
95%
CO2H
d
90% (17, 18, 19)
OH
OH
(CH2)3CO2H
CO2H
(CH2)3CO2H
(CH2)3R'
ROC
HO
+
+
N
N
N
H
H
H
18
19
17, R = OH; R' = CO2H
48% e
62% f
91% g
20, R = OMe; R' = CO2Me
21, R = OMe; R' = CH2OH
22, R = NH2; R' = CH2OH
CONH2
h
60%
(CH2)4OR'
O
(CH2)4
N
N
NC
NC
RO
i
77%
N
H
N
RO
H
24, R = Mes
3, R = H
23, R = Mes; R' = Mes
20% j
Scheme 2. Synthesis of metabolite 3. Reagents and conditions: (a) (i) 11, HCl, NaNO2, 0 °C; (ii) ethyl 2-oxo-cyclohexanone carboxylate 5, H2O,
KOH; (b) CH3CO2H, H2SO4; 120 °C; (c) NaOH, H2O, 80 °C; (d) KOH, H2O; 280 °C; (e) MeOH, cat. H2SO4; (f) LiAlH4, THF; (g) MeOH, NH3–
H2O (25%); (h) DCM/THF, MeSO2Cl, TEA, 0 °C to rt; (i) 5-piperazin-1-yl-benzofuran-2-carboxamide, NMP, 120 °C; (j) KOH, MeOH.
alcohol and protection of the aromatic 6-hydroxy-
function on the indole as di-mesylate 23. Alkylation of
5-piperazin-1-yl-benzofuran-2-carboxamide with this
di-mesylate 23 led to precursor 24. In the final step
selective cleavage of the remaining 6-indolyl mesylate by
potassium hydroxide in methanol and usual work-up
gave the free base of 3 in 0.8% overall yield.12
References and notes
1. (a) Sundberg, R. J. Indoles; Academic: London, 1996; (b)
Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045;
(c) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001,
2491.
2. (a) Seyfried, C. A.; Fuxe, K.; Wolf, H.-P.; Agnati, L. F.
Acta Physiol. Scand. 1982, 116, 465; (b) Hausberg, H.-H.;
€
Bottcher, H.; Fuchs, A.; Gottschlich, R.; Koppe, V.;
With the application of the Japp–Klingemann indole
synthesis, starting off with unprotected 4-amino salicylic
acid, we were able to prepare for the first time sub-
stantial amounts of the unusual hydroxylated metabo-
lite of vilazodone. This hydroxylation led to a significant
decrease in the important dual activity profile of
vilazodone. Furthermore, it could be shown, that the
decarboxylation of indole-2-carboxylic acids depends on
the substitution pattern of the indole nucleus. Besides
the selective decarboxylation several alkaline steps could
be performed successfully to distinguish the different
aliphatic and aromatic hydroxy and acid functions.
Efforts are ongoing in our group to prepare further
indole derivatives with an aromatic substitution pattern
as found in salicylic acid.
Minck, K.-O.; Poetsch, E.; Saiko, O.; Seyfried, C. A. Acta
Pharm. Suec. (Suppl.) 1983, 2, 213; (c) Bartoszyk, G. D.;
Harting, J.; Minck, K.-O. J. Pharmacol. Exp. Ther. 1996,
276, 41; (d) Seyfried, C. A.; Greiner, H. E.; Haase, A. F.
Eur. J. Pharmacol. 1998, 160, 31; (e) Lange, J. H. M.;
de Jong, J. C.; Sanders, H. J.; Visser, G. M.; Kruse,
C. G. Bioorg. Med. Chem. Lett. 2003, 13, 3087; (f)
€
Bottcher, H.; Barnickel, G.; Hausberg, H. H.; Haase, A.
F.; Seyfried, C. A.; Eiermann, V. J. Med. Chem. 2002, 42,
4020.
3. (a) Haase, A. F.; Greiner, H. E.; Seyfried, C. A. Naunyn-
Schmiedebergs Arch. Phamacol. 1991, 343, 588; (b)
€
Bottcher, H.; Gericke, R. Liebigs Ann. Chem. 1988, 149.
4. Bartoszyk, G. D.; Hegenbart, R.; Ziegler, H. Eur. J.
Pharmacol. 1997, 322, 147.
5. Seyfried, C. A.; Bottcher, H. Drugs Future 1990, 15, 819.
€
€
6. Hewitt, N. J.; Buhring, K.-U.; Dasenbrock, J.; Haun-
schild, J.; Ladstetter, B.; Utesch, D. Drug Metab. Dispos.
2001, 29, 1042.
Acknowledgements
7. For 6-methoxy-1H-indolyl-5-carboxamides see, for exam-
ple: Mavunkel, B. J.; Chakravarty, S.; Perumattam, J. J.;
Luedtke, G. R.; Liang, X.; Lim, D.; Xu, Y.-j.; Laney, M.;
Liu, D. Y.; Schreiner, G. F.; Lewicki, J. A.; Dugar, S.
Bioorg. Med. Chem. Lett. 2003, 13, 3087.
The authors thank Prof. Ekkehard Winterfeldt for his
encouraging discussions and Kurt Schuster and Bernd
Arzt for technical assistance.